Under certain conditions, NO synthesis is disturbed, and this may contribute to the progression of atherosclerosis, and impair angiogenic response. The impairment of the NO synthase pathway may be due in part to an endogenous NOS inhibitor ADMA (asymmetric dimethylarginine). In patients with peripheral arterial disease (PAD), ADMA levels are elevated. In these individuals L-arginine enhances NO synthesis and improves limb blood flow. Our proposal is designed to determine if chronic administration of L-arginine will cause a sustained enhancement of limb blood flow, and will reduce symptoms in individuals with PAD. We will also determine if these effects are accompanied by anti- atherogenic and/or pro-angiogenic effects of NO biosynthesis. Patients with PAD will be entered into a randomized placebo-controlled clinical trial to assess the effects of L-arginine upon functional status (treadmill exercise testing; quality of life) and limb blood (by mercury strain gauge plethysmography). We will determine if NO biosynthesis is involved in the effects of L-arginine by: function of duplex ultrasonography of flow-mediated vasodilation. We will assess limb hemodynamics (by Doppler-derived pressures, plethysmography, and by MR perfusion imaging), conduit vessel structure (using magnetic resonance angiography); and evidence of angiogenesis using novel MR algorithms (to include flow-independent imaging, manipulation, manipulation of 3-dimensional data sets, and use of oxygen saturation effects on T2 relaxation time). These studies will determine if prolonged L-arginine treatment may have effects upon vascular structure, lesion size and/or angiogenesis. These studies may lead to a novel and cost-effective strategy for treatment of peripheral arterial disease.